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OBJECTIVE: Oral candidiasis is a common fungal infection that affects the oral mucosa, and happens when Candida albicans interacts with bacteria in the oral microbiota, such as Streptococcus mutans, causing severe early childhood caries. C. albicans and S. mutans mixed biofilms are challenging to treat with conventional antimicrobial therapies, thus, new anti-infective drugs are required. This study aimed to test a drug delivery system based on chitosan microparticles loaded with geranium and lemongrass essential oils to inhibit C. albicans and S. mutans mixed biofilms. METHODOLOGY: Chitosan microparticles loaded with essential oils (CM-EOs) were obtained by spray-drying. Susceptibility of planktonic were performed according CLSI at 4 to 2,048 µg/mL. Mixed biofilms were incubated at 37ºC for 48 h and exposed to CM-EOs at 256 to 4,096 µg/mL. The antimicrobial effect was evaluated using the MTT assay, with biofilm architectural changes analyzed by scanning electron microscopy. RAW 264.7 cell was used to evaluate compound cytotoxicity. RESULTS: CM-EOs had better planktonic activity against C. albicans than S. mutans. All samples reduced the metabolic activity of mixed C. albicans and S. mutans biofilms, with encapsulated oils showing better activity than raw chitosan or oils. The microparticles reduced the biofilm on the slides. The essential oils showed cytotoxic effects against RAW 264.7 cells, but encapsulation into chitosan microparticles decreased their toxicity. CONCLUSION: This study demonstrates that chitosan loaded with essential oils may provide an alternative method for treating diseases caused by C. albicans and S. mutans mixed biofilm, such as dental caries.
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Quitosana , Cárie Dentária , Óleos Voláteis , Pré-Escolar , Humanos , Óleos Voláteis/farmacologia , Candida albicans , Streptococcus mutans , Quitosana/farmacologia , Cárie Dentária/prevenção & controle , BiofilmesRESUMO
The limited therapeutic options for fungal infections and the increased incidence of fungal strains resistant to antifungal drugs, especially Candida spp., require the development of new antifungal drugs and strategies. Histone deacetylase inhibitors (HDACi), like vorinostat, have been studied in cancer treatment and have antifungal effects, acting alone or synergistically with classical antifungals. Here we investigated the antifungal activity of two novel sustainable HDACi (LDT compounds) based on vorinostat structure. Molecular docking simulation studies reveal that LDT compounds can bind to Class-I HDACs of Candida albicans, C. tropicalis, and Cryptococcus neoformans, which showed similar binding mode to vorinostat. LDT compounds showed moderate activity when tested alone against fungi but act synergistically with antifungal azoles against Candida spp. They reduced biofilm formation by more than 50% in C. albicans (4 µg/mL), with the main action in fungal filamentation. Cytotoxicity of the LDT compounds against RAW264.7 cells was evaluated and LDT536 demonstrated cytotoxicity only at the concentration of 200 µmol/L, while LDT537 showed IC50 values of 29.12 µmol/L. Our data indicated that these sustainable and inexpensive HDACi have potential antifungal and antibiofilm activities, with better results than vorinostat, although further studies are necessary to better understand the mechanism against fungal cells.
Fungal infections are neglected diseases that affect more than a billion people worldwide. Some histone deacetylase inhibitors can act against fungal cells. Our data reveal that HDACi LDT536 and LDT537 have potential antibiofilm and antifungal activities.
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Five unusual kaurane diterpenes, designated as bezerraditerpenes A-E (1-5), along with six known ones (6-11), were isolated from the hexane extract of the stems of Erythroxylum bezerrae. Their structures were elucidated based on the interpretation of the NMR spectroscopy, mass spectrometry, and X-ray diffraction analysis. The anti-inflammatory potential of the diterpenes 1-11 was screened through cellular viability and lipopolysaccharide (LPS)-induced nitric oxide (NO) production on murine macrophage-like cells RAW 264.7. Diterpene 6 (cauren-6ß-ol) showed potent cytotoxicity and increased ability to inhibit NO production. Diterpenes 1 (bezerraditerpene A), 2 (bezerraditerpene B), and 8 (ent-kaur-16-ene-3ß,15ß-diol) exhibited the same significant anti-inflammatory activity with NO CI50 inhibition (3.21-3.76 µM) without cytotoxicity, in addition to decreasing the levels of pro-inflammatory cytokines TNF-α and IL-6 in LPS-induced RAW264.7 cells.
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Diterpenos do Tipo Caurano , Diterpenos , Animais , Camundongos , Anti-Inflamatórios/farmacologia , Diterpenos/farmacologia , Diterpenos do Tipo Caurano/farmacologia , Diterpenos do Tipo Caurano/química , Lipopolissacarídeos/farmacologia , Estrutura Molecular , Óxido Nítrico , Erythroxylaceae/químicaRESUMO
Abstract Oral candidiasis is a common fungal infection that affects the oral mucosa, and happens when Candida albicans interacts with bacteria in the oral microbiota, such as Streptococcus mutans, causing severe early childhood caries. C. albicans and S. mutans mixed biofilms are challenging to treat with conventional antimicrobial therapies, thus, new anti-infective drugs are required. Objective This study aimed to test a drug delivery system based on chitosan microparticles loaded with geranium and lemongrass essential oils to inhibit C. albicans and S. mutans mixed biofilms. Methodology Chitosan microparticles loaded with essential oils (CM-EOs) were obtained by spray-drying. Susceptibility of planktonic were performed according CLSI at 4 to 2,048 µg/mL. Mixed biofilms were incubated at 37ºC for 48 h and exposed to CM-EOs at 256 to 4,096 µg/mL. The antimicrobial effect was evaluated using the MTT assay, with biofilm architectural changes analyzed by scanning electron microscopy. RAW 264.7 cell was used to evaluate compound cytotoxicity. Results CM-EOs had better planktonic activity against C. albicans than S. mutans. All samples reduced the metabolic activity of mixed C. albicans and S. mutans biofilms, with encapsulated oils showing better activity than raw chitosan or oils. The microparticles reduced the biofilm on the slides. The essential oils showed cytotoxic effects against RAW 264.7 cells, but encapsulation into chitosan microparticles decreased their toxicity. Conclusion This study demonstrates that chitosan loaded with essential oils may provide an alternative method for treating diseases caused by C. albicans and S. mutans mixed biofilm, such as dental caries.
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Withajardins, uncommon modified withanolide-type steroids, have been isolated exclusively from plants of the Solanaceae family so far. Two undescribed withajardins and the known tuboanosigenin were isolated from the hexane/EtOAc 1:1 extract from Athenaea velutina leaves. Their structures were established by an extensive analysis of 1D and 2D-NMR and HRMS data. The absolute configuration was determined by X-ray diffraction (withajardin L and tuboanosigenin) and circular dichroism (CD) analyses (withajardin M). The anti-inflammatory activity of compounds was evaluated through the inhibition of the lipopolysaccharide (LPS)-induced nitric oxide (NO), TNF-α, and IL-6 release in RAW264.7 cells. The cell viability effects to RAW 264.7 cells showed IC50 values of 74.4-354.4 µM. The compounds attenuated LPS-induced release of NO and decreased pro-inflammatory cytokines TNF-α and IL-6 in RAW264.7 cells.
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Anti-Inflamatórios , Extratos Vegetais , Solanaceae , Vitanolídeos , Animais , Anti-Inflamatórios/química , Anti-Inflamatórios/farmacologia , Interleucina-6 , Lipopolissacarídeos , Camundongos , Óxido Nítrico , Extratos Vegetais/química , Extratos Vegetais/farmacologia , Células RAW 264.7 , Solanaceae/química , Fator de Necrose Tumoral alfa , Vitanolídeos/química , Vitanolídeos/farmacologiaRESUMO
This study aimed to evaluate the effect of proteinase K on mature biofilms of dermatophytes, by assays of metabolic activity and biomass. In addition, the proteinase K-terbinafine and proteinase K-griseofulvin interactions against these biofilms were investigated by the checkerboard assay and scanning electron and confocal microscopy. The biofilms exposed to 32 µg ml-1 of proteinase K had lower metabolic activity and biomass, by 39% and 38%, respectively. Drug interactions were synergistic, with proteinase K reducing the minimum inhibitory concentration of antifungals against dermatophyte biofilms at a concentration of 32 µg ml-1 combined with 128-256 µg ml-1 of terbinafine and griseofulvin. Microscopic images showed a reduction in biofilms exposed to proteinase K, proteinase K-terbinafine and proteinase K-griseofulvin combinations. These findings demonstrate that proteinase K has activity against biofilms of dermatophytes, and the interactions of proteinase K with terbinafine and griseofulvin improve the activity of drugs against mature dermatophyte biofilms.
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Antifúngicos , Arthrodermataceae , Antifúngicos/farmacologia , Biofilmes , Endopeptidase K/farmacologia , Griseofulvina/farmacologia , Testes de Sensibilidade Microbiana , Terbinafina/farmacologiaRESUMO
BACKGROUND: Leishmania braziliensis is prevalent in Latin American countries, including Brazil. It causes cutaneous and mucocutaneous leishmaniasis, leading to high morbidity, and has a low cure rate. Treatment is based on pentavalent antimonials; nonetheless, there are problems related to high toxicity, high cost, and parasitic resistance. Discovery of new leishmanicidal drugs without these limitations and that stimulate the cellular immune response is necessary. PURPOSE: The present work evaluates whether Astronium fraxinifolium Schott exerts leishmanicidal activity against L. braziliensis by providing a classically polarized profile in infected macrophages. METHODS: For the evaluation of the A. fraxinifolium Schott leishmanicidal activity, amastigote cell death was demonstrated in infected RAW 267.4 macrophages treated with an ethanolic extract from the plant sapwood (EEAF). For the evaluation of the EEAF capacity in providing a classically polarized profile in infected macrophages, the following analyses were done: detection of LAMP-1 protein by the baculovirus technology, measurement of superoxide anion by the NBT testing, quantification of TNF-α, IL-12p40, IL-10, IL-4, and TGF-ß by sandwich-type enzyme immune assays, and iNOS and COX-2 expression by RT-PCR technique. RESULTS: The EEAF significantly reduced amastigote counts inside the cells. Vacuoles were visualized in infected and treated cells before and after May-Grünwald-Giemsa staining. A strong LAMP-1 protein fluorescence revealed phagosome maturation in infected cells treated with the EEAF. No production of superoxide was visualized in infected cells treated with the plant material. Nonetheless, high levels of TNF-α, IL-12p40, and IL-10 were found in cell supernatants, but reduced levels of TGF-ß and no IL-4 production. We identified augmented mRNA expression for COX-2, but no expression of iNOS mRNA. CONCLUSION: Our results demonstrated that A. fraxinifolium induced a classically polarized profile in infected macrophages but also provided a less harmful environment by stimulating the production of certain anti-inflammatory mediators, such as IL-10.
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Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Extratos Vegetais/farmacologia , Anacardiaceae/química , Animais , Sobrevivência Celular/efeitos dos fármacos , Citocinas/análise , Citocinas/imunologia , Interleucina-10/análise , Macrófagos/parasitologia , Camundongos , Células RAW 264.7RESUMO
Inflammation is a physiological process triggered in response to tissue damage, and involves events related to cell recruitment, cytokines release and reactive oxygen species (ROS) production. Failing to control the process duration lead to chronification and may be associated with the development of various pathologies, including autoimmune diseases and cancer. Considering the pharmacological potential of metal-based compounds, two new ruthenium complexes were synthesized: cis-[Ru(NO2)(bpy)2(5NIM)]PF6 (1) and cis-[RuCl(bpy)2(MTZ)]PF6 (2), where bpyâ¯=â¯2,2'-bipyridine, 5NIMâ¯=â¯5-nitroimidazole and MTZâ¯=â¯metronidazole. Both products were characterized by spectroscopic techniques, followed by Density Functional Theory (DFT) calculations in order to support experimental findings. Afterwards, their in vitro cytotoxic, antioxidant and anti-inflammatory activities were investigated. Compounds 1 and 2 presented expressive in vitro antioxidant activity, reducing lipid peroxidation and decreasing intracellular ROS levels with comparable effectiveness to the standard steroidal drug dexamethasone or α-tocopherol. These complexes showed no noticeable cytotoxicity on the tested cancer cell lines. Bactericidal assay against metronidazole-resistant Helicobacter pylori, a microorganism able to disrupt oxidative balance, unraveled compound 1 moderate activity over that strain. Besides this, it was able to inhibit interleukin-6 (IL-6) and tumor necrosis factor-α (TNF- α) production as well as interleukin-1ß (IL-1ß) and cyclooxygenase-2 (COX-2) expression in lipopolysaccharide (LPS)-stimulated RAW264.7 macrophages. This latter activity is remarkable, which has not been reported for other ruthenium-based complexes. Altogether, these results suggest cis-[Ru(NO2)(bpy)2(5NIM)]PF6 complex has potential pharmacological application as an anti-inflammatory agent that deserve further biological investigation.
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Antibacterianos/farmacologia , Anti-Inflamatórios/farmacologia , Antineoplásicos/farmacologia , Antioxidantes/farmacologia , Complexos de Coordenação/farmacologia , Imidazóis/química , Rutênio/química , Células A549 , Animais , Antibacterianos/química , Anti-Inflamatórios/química , Antineoplásicos/química , Antioxidantes/química , Bactérias/efeitos dos fármacos , Proliferação de Células , Complexos de Coordenação/química , Humanos , Peroxidação de Lipídeos , Células MCF-7 , Camundongos , Estrutura Molecular , Células RAW 264.7 , Superóxidos/metabolismoRESUMO
Arthur de Carvalho Drops® (ACD) is a traditional Brazilian herbal medicine used to treat functional gastrointestinal disorders (FGIDs). ACD is a formulation of herbal extracts from Matricaria recutita (chamomile), Foeniculum vulgare (fennel) and Gentiana lutea L. (gentian). Considering the popular use for FGIDs, the aim of this work was to investigate the ACD effect on gastric and intestinal parameters with emphasis in a mechanistic approach using isolated duodenal preparations of rodents. Analytical method was developed and validated for quantify three actives principles/markers (Apigenin-7-glucoside, gentiopicroside and anethole) in ACD. The treatment with ACD significantly reduced the emetogenic stimuli induced by cisplatin in rats, showed a laxative effect, reduced the bethanechol-enhanced gastrointestinal transit and completely reversed the contraction induced by carbachol in rat duodenum. However, ACD did not alter the secretory gastric volume or total gastric acidity. The ACD affect the contractions of duodenal smooth muscle mediated by Ca2+ channels and it is also able to inhibit the contractile response mediated by the release from its intracellular store. Furthermore, the relaxant effects of ACD appear independent of the nitric oxide pathway in rat duodenum. These results suggest that ACD could be beneficial for the treatment of disorders of the gastrointestinal tract.
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Wound healing involves the interaction of blood cells, proteins, proteases, growth factors, and extracellular matrix components. Inflammation is one of the first events occurring during this process. Previously, we showed that the N-Methyl-(2S,4R)-trans-4-Hydroxy-L-Proline (NMP) from Sideroxylon obtusifolium leaves (a Brazilian medicinal species) presents an anti-inflammatory action. Considering inflammation as an important event in the wound healing process, the objectives were to investigate the topical effects of the NMP gel on a mice wound-induced model. Male Swiss mice were divided into 4 groups: Sham (surgical procedure only), Control (gel-base treated), and 3% or 10% NMP gel-treated groups. Measurements of wound areas and microscopic analyses (HE [hematoxylin-eosin] and PSR [picrosirius red] stainings) were carried out, at the 7th and 12th, days after the wound induction. Furthermore, immunohistochemical assays for iNOS (inducible nitric oxide synthase) and COX-2 (cyclooxygenase-2) and biochemical measurements for TBARS (thiobarbituric acid reactive substances), GSH (glutathione), and myeloperoxidase (MPO) were also performed, at the second day after the wound induction. The work showed that NMP decreases the wound areas, after topical application, relatively to the Sham and Control groups. In addition, microscopic alterations were reduced and collagen deposition was increased, at the 7th and 12th days, in the 10% NMP group. While iNOS and COX-2 immunostainings and GSH contents increased, in relation to the Sham and Control groups, TBARS and MPO decreased. Altogether, the results showed NMP to improve the wound healing process, by upregulating iNOS and COX-2 activities, reducing lipid peroxidation and MPO activity, and increasing GSH contents. In addition, NMP certainly contributes to the increased collagen deposition. These data may stimulate translational studies dealing with the possible use of NMP from Sideroxylon obtusifolium or from other sources for the management of wound healing.
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Anti-Inflamatórios/administração & dosagem , Antioxidantes/administração & dosagem , Extratos Vegetais/administração & dosagem , Prolina/administração & dosagem , Sapotaceae/química , Cicatrização/efeitos dos fármacos , Ferimentos e Lesões/tratamento farmacológico , Animais , Anti-Inflamatórios/química , Antioxidantes/química , Colágeno/genética , Colágeno/imunologia , Ciclo-Oxigenase 2/genética , Ciclo-Oxigenase 2/imunologia , Glutationa/imunologia , Humanos , Masculino , Camundongos , Óxido Nítrico Sintase Tipo II/genética , Óxido Nítrico Sintase Tipo II/imunologia , Peroxidase/genética , Peroxidase/imunologia , Extratos Vegetais/química , Prolina/análogos & derivados , Ferimentos e Lesões/genética , Ferimentos e Lesões/imunologia , Ferimentos e Lesões/fisiopatologiaRESUMO
Dietary fiber intake plays an important role in the prevention of obesity. This study aimed at investigating the effect of cashew fiber without low molecular weight compounds (CABwc) on obesity prevention and metabolomics in a murine model of diet-induced obesity. Mice were fed a chow diet (CD), a high-fat diet (HFD) or a high-fat diet supplemented with CABwc (10%) (HFD-CABwc) for 15 weeks. The body weight, abdominal fat, serum glucose levels, insulin and lipid profiles, satiety hormones such as leptin and ghrelin, digestive enzymes such as amylase and lipase, and inflammatory mediators such as TNF-α, IL-6, and adiponectin were measured, in addition to performing serum and hepatic tissue analyses. The metabolomic analysis was based on nuclear magnetic resonance (NMR) spectroscopy of serum and feces. The effects observed with ingestion of CABwc were appetite control and prevention of hyperglycemia, hyperinsulinemia and hypertriglyceridemia, as well as the prevention of the inflammatory process and reduction of liver injury caused by the HFD. In addition, NMR evidenced the presence of SCFAs in serum and feces of mice fed with HFD-CABwc. These findings suggest that CABwc promoted satiety in mice, improving the metabolism of glucose and lipids. Positive effects of obesity prevention may be associated with SCFA production.
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Anacardium/química , Dieta Hiperlipídica/efeitos adversos , Fibras na Dieta/farmacologia , Obesidade/induzido quimicamente , Obesidade/prevenção & controle , Animais , Fibras na Dieta/análise , Suplementos Nutricionais , Fezes/química , Espectroscopia de Ressonância Magnética , Metabolômica , Camundongos , Obesidade/sangueRESUMO
Previous studies have reported the anti-obesity effects of α, ß-Amyrin in high fat-fed mice. This study aimed to evaluate whether α, ß-Amyrin has an anti-adipogenic effect in 3T3-L1 murine adipocytes and to explore the possible underlying mechanisms. 3T3-L1 pre-adipocytes were differentiated in a medium containing insulin, dexamethasone, and 1-methyl-3-isobutylxanthine. Cytotoxicity of α, ß-Amyrin was assessed by MTT assay. Lipid content in adipocytes was determined by Oil-Red O staining. In addition, the protein expression levels of peroxisome proliferator-activated receptor gamma (PPARγ), CCAAT/enhancer binding proteins alpha (C/EBPα), beta (C/EBPß), and delta (C/EBPδ) and glucose transporter 4 (GLUT4) were determined by qRT-PCR and western blot analysis. Oil-Red O staining revealed markedly reduced fat accumulation by α, ß-Amyrin (6.25-50 µg/mL) without affecting cell viability. Furthermore, our results indicate that α, ß-Amyrin can significantly suppress the adipocyte differentiation by downregulating the expression levels of adipogenesis-related key transcription factors such as PPARγ and C/EBPα, but not C/EBPß or C/EPBδ. In addition, the protein expression of membrane GLUT4 in 3T3- L1 adipocytes treated with α, ß-Amyrin was significantly higher than in control cells, indicating that α, ß-Amyrin augments glucose uptake. These findings suggest that α, ß-Amyrin exerts an anti-adipogenic effect principally via modulation of lipid and carbohydrate metabolism in 3T3-L1cells. The present in vitro findings, taken together with our earlier observation of the anti-obesity effect in vivo, suggest that α, ß-Amyrin can be developed as a new therapeutic agent for treatment and prevention of obesity.
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Adipócitos/efeitos dos fármacos , Proteína alfa Estimuladora de Ligação a CCAAT/metabolismo , Diferenciação Celular/efeitos dos fármacos , Regulação para Baixo/efeitos dos fármacos , Ácido Oleanólico/análogos & derivados , PPAR gama/metabolismo , Triterpenos Pentacíclicos/farmacologia , Células 3T3-L1 , Adipogenia/efeitos dos fármacos , Animais , Proteína beta Intensificadora de Ligação a CCAAT/metabolismo , Linhagem Celular , Sobrevivência Celular/efeitos dos fármacos , Proteínas de Ligação a Ácido Graxo/metabolismo , Transportador de Glucose Tipo 4/metabolismo , Camundongos , Obesidade/tratamento farmacológico , Obesidade/metabolismo , Ácido Oleanólico/farmacologia , Extratos Vegetais/farmacologiaRESUMO
To characterize the protective effects of the triterpenoid mixture alpha, beta-amyrin (AMY, 20 mg/kg, during 15 days) on the reactivity of isolated aorta of high-fat diet (HFD)-induced obese mice. Male Swiss mice were fed with HFD or normal diet (ND) for 15 weeks. Contractions of thoracic aorta in response to KCl or phenylephrine (PHE) and relaxation by acetylcholine (ACh) or sodium nitroprusside (SNP) were analyzed. HFD-fed mice developed hyperglycemia, hyperlipidemia, and significant body weight gain, parameters prevented by AMY treatment. Whereas aortic contractility did not differ in response to KCl, contractions induced by PHE (1 µM) as well as relaxation induced by ACh (1-30 µM) or SNP (1 nM-0.1 mM) on PHE-contracted aorta were decreased (p < 0.05) in tissues of HFD compared to ND mice, phenomenon significantly (p < 0.05) diminished in HFD mice treated with AMY. The relaxant actions of ACh and SNP were inhibited (p < 0.05) by tetraethylammonium (TEA, 5 mM), apamin (0.1 µM), and 4-aminopyridine (4-AP; 3 mM) in aortae from ND group, but not from HFD. Treatment of HFD mice with AMY rescued the inhibitory effect of TEA (p < 0.05) on vasorelaxant actions of ACh and SNP. 1H-[1,2,4]oxadiazolo[4,3-a]quinoxalin-1-one (ODQ) inhibited similarly the relaxant effects of SNP in all groups. 8-Br-cGMP relaxed with similar profile aortae of all groups. By preventing HFD-induced obesity in mice, AMY rescued the blunted contractile response to PHE, and the attenuated vasorelaxation and K+ channel activation (opening) induced by ACh and SNP in isolated aorta.
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Aorta Torácica/efeitos dos fármacos , Dieta Hiperlipídica/efeitos adversos , Obesidade/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Vasoconstrição/efeitos dos fármacos , Vasodilatação/efeitos dos fármacos , Animais , Aorta Torácica/fisiologia , Peso Corporal/efeitos dos fármacos , Peso Corporal/fisiologia , Relação Dose-Resposta a Droga , Endotélio Vascular/efeitos dos fármacos , Endotélio Vascular/fisiologia , Masculino , Camundongos , Obesidade/etiologia , Obesidade/fisiopatologia , Ácido Oleanólico/farmacologia , Ácido Oleanólico/uso terapêutico , Triterpenos/farmacologia , Triterpenos/uso terapêutico , Vasoconstrição/fisiologia , Vasodilatação/fisiologiaRESUMO
Obesity remains a global problem. In search of phytochemicals that have antiobesity potential, this study evaluated α,ß-amyrin, a triterpenoid mixture from Protium heptaphyllum, on high-fat diet-induced obesity in mice. Groups of mice (n = 8) were fed a normal diet or a high-fat diet, and were orally treated or not treated with either α,ß-amyrin (10 or 20 mg/kg) or sibutramine (10 mg/kg) for 15 weeks. Variables measured at termination were body weight, visceral fat accumulation, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions in adipose tissue, the levels of plasma glucose and insulin, the satiety hormones ghrelin and leptin, the digestive enzymes amylase and lipase, and the inflammatory mediators TNF-α, interleukin-6, and MCP-1. Results showed that α,ß-amyrin treatment resulted in lower high-fat diet-induced increases in body weight, visceral fat content, adipocyte surface area, peroxisome proliferator-activated receptor gamma, and lipoprotein lipase expressions, and blood glucose and insulin levels. Additionally, the markedly elevated leptin and decreased ghrelin levels seen in the high-fat diet-fed control mice were significantly modulated by α,ß-amyrin treatment. Furthermore, α,ß-amyrin decreased serum TNF-α and MCP-1. These results suggest that α,ß-amyrin could be beneficial in reducing high-fat diet-induced obesity and associated disorders via modulation of enzymatic, hormonal, and inflammatory responses.
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Fármacos Antiobesidade/farmacologia , Obesidade/tratamento farmacológico , Ácido Oleanólico/análogos & derivados , Gordura Abdominal/efeitos dos fármacos , Adipócitos/citologia , Adipócitos/efeitos dos fármacos , Tecido Adiposo/efeitos dos fármacos , Tecido Adiposo/metabolismo , Tecido Adiposo Branco/efeitos dos fármacos , Animais , Glicemia/metabolismo , Peso Corporal/efeitos dos fármacos , Burseraceae/química , Ciclobutanos/farmacologia , Dieta Hiperlipídica , Grelina/sangue , Insulina/sangue , Leptina/sangue , Lipídeos/sangue , Lipase Lipoproteica/metabolismo , Masculino , Camundongos , Obesidade/sangue , Obesidade/etiologia , Ácido Oleanólico/química , Ácido Oleanólico/isolamento & purificação , Ácido Oleanólico/farmacologia , PPAR gama/metabolismo , Fitoterapia , Resistina/sangueRESUMO
BACKGROUND: Major thoracic surgery is characterized by release of inflammatory markers.The objective of this study was to assess the preoperative and postoperative systemic inflammatory markers of patients undergoing lung cancer resection. METHODS: This is a prospective follow up study conducted with 48 patients submitted to lung cancer resection.All patients were assessed before and 1 month after surgery through measurement of fibrinogen and C-reative protein(CRP), pulmonary function tests, 6- minute Walk Test (6 MWT), maximal inspiratory pressure (PImax) and maximal expiratory pressure (PEmax), anxiety and depression scale and karnofsky performance status scale. RESULTS: Both fibrinogen and CRP were higher 1 month after surgery, although only the change in CRP was statistically significant (p= 0.03). The following functional parameters: 6 MWT, PImax, PEmax, FEV1(%) and FVC(%) decreased after surgery with p ≤ 0.001 for all the parameters. Anxiety and depression improved and Karnofsky decrease after surgery (p= 0.03, p= 0.01 and p= 0.02; respectively). Change in CRP score following lung resection correlated significantly with changes in fibrinogen (r= 0.40; p= 0.003), change in Karnofsky scale (r= -0.50; p< 0.001) and a borderline significant trend with the 6 MWT (r= -0.28; p= 0.05). With the exception of video-assisted thoracoscopic surgery (VATS), who had a significantly lower fibrinogen level 1 month after surgery compared with thoracotomy (p= 0.01), no significant differences in fibrinogen or CRP were noted in other subgroups of patients considered at increased risk for higher levels of inflammation compared with lower risk counterparts. CONCLUSION: Lung cancer resection surgery was associated with increased level of CRP, 1 month after surgery, and correlated directly with change in fibrinogen and inversely with measurement of performance status. VATS provided lower level of fibrinogen after surgery.
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Biomarcadores/sangue , Proteína C-Reativa , Fibrinogênio , Neoplasias Pulmonares/sangue , Neoplasias Pulmonares/cirurgia , Idoso , Terapia Combinada , Comorbidade , Citocinas/sangue , Feminino , Seguimentos , Humanos , Mediadores da Inflamação/sangue , Neoplasias Pulmonares/diagnóstico , Neoplasias Pulmonares/mortalidade , Masculino , Pessoa de Meia-Idade , Estadiamento de Neoplasias , Estudos Prospectivos , Testes de Função Respiratória , Resultado do TratamentoRESUMO
Herbal compounds rich in triterpenes are well known to regulate glucose and lipid metabolism and to have beneficial effects on metabolic disorders. The present study investigated the antiobesity properties of resin from Protium heptaphyllum (RPH) and the possible mechanisms in mice fed a high-fat diet (HFD) for 15 weeks. Mice treated with RPH showed decreases in body weight, net energy intake, abdominal fat accumulation, plasma glucose, amylase, lipase, triglycerides, and total cholesterol relative to their respective controls, which were RPH unfed. Additionally, RPH treatment, while significantly elevating the plasma level of ghrelin hormone, decreased the levels of insulin, leptin, and resistin. Besides, HFD-induced increases in plasma levels of proinflammatory mediators TNF-α, IL-6, and MCP-1 were significantly lowered by RPH. Furthermore, in vitro studies revealed that RPH could significantly inhibit the lipid accumulation in 3T3-L1 adipocytes (measured by Oil-Red O staining) at concentrations up to 50 µg/mL. These findings suggest that the antiobese potential of RPH is largely due to its modulatory effects on various hormonal and enzymatic secretions related to fat and carbohydrate metabolism and to the regulation of obesity-associated inflammation.
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Our previous study has shown that mangiferin (MGF), a glucosylxanthone from Mangifera indica, exerts gastrointestinal prokinetic action involving a cholinergic mechanism. Postoperative ileus (POI) is a temporary disturbance in gastrointestinal motility following surgery, and intestinal inflammatory response plays a critical role in the pathogenesis of POI. The present study investigated to know whether MGF having anti-inflammatory and prokinetic actions can ameliorate the intestinal inflammation and impaired gastrointestinal transit seen in the mouse model of POI. Experimental POI was induced in adult male Swiss mice by standardized small intestinal manipulation (IM). Twenty-four hours later, gastrointestinal transit was assessed by charcoal transport. MGF was administered orally 1 h before the measurement of GIT. To evaluate the inflammatory response, plasma levels of proinflammatory cytokines TNF-α, IL-1ß, IL-6, and chemokine MCP-1, and the myeloperoxidase activity, nitrate/nitrite level, and histological changes of ileum were determined in mice treated or not with MGF. Experimental POI in mice was characterized by decreased gastrointestinal transit and marked intestinal and systemic inflammatory response. MGF treatment led to recovery of the delayed intestinal transit induced by IM. MGF in ileum significantly inhibited the myeloperoxidase activity, a marker of neutrophil infiltration, and nitrate/nitrite level and reduced the plasma levels of TNF-α, IL-1ß, IL-6, and MCP-1 as well. MGF treatment ameliorates the intestinal inflammatory response and the impaired gastrointestinal motility in the mouse model of POI.
Assuntos
Enterocolite/prevenção & controle , Fármacos Gastrointestinais/uso terapêutico , Motilidade Gastrointestinal/efeitos dos fármacos , Íleus/prevenção & controle , Complicações Pós-Operatórias/prevenção & controle , Xantonas/uso terapêutico , Animais , Citocinas/sangue , Modelos Animais de Doenças , Enterocolite/etiologia , Enterocolite/imunologia , Enterocolite/patologia , Fármacos Gastrointestinais/administração & dosagem , Fármacos Gastrointestinais/isolamento & purificação , Íleo/efeitos dos fármacos , Íleo/imunologia , Íleo/patologia , Íleus/etiologia , Íleus/imunologia , Íleus/patologia , Masculino , Mangifera/química , Camundongos , Casca de Planta/química , Raízes de Plantas/química , Complicações Pós-Operatórias/etiologia , Complicações Pós-Operatórias/imunologia , Complicações Pós-Operatórias/patologia , Xantonas/administração & dosagem , Xantonas/isolamento & purificaçãoRESUMO
AIMS: Acute pancreatitis (AP) is an inflammatory condition wherein pro-inflammatory mediators, oxidative stress, and NF-κB signaling play a key role. Currently, no specific therapy exists and treatment is mainly supportive and targeted to prevent local pancreatic injury and systemic inflammatory complications. This study was aimed to examine whether 1,8-cineole, a plant monoterpene with antioxidant and anti-inflammatory properties could ameliorate cerulein-induced acute pancreatitis. MAIN METHODS: AP was induced in Swiss mice by six one hourly injections of cerulein (50 µg/kg, i.p.). 1,8-cineole (100, 200 and 400mg/kg, p.o.) was administered 1h prior to first cerulein injection, keeping vehicle and thalidomide treated groups as controls. Blood samples were taken 6-h later to determine serum levels of amylase and lipase, and cytokines. The pancreas was removed for morphological examination, myeloperoxidase (MPO) and malondialdehyde (MDA) assays, reduced glutathione (GSH) levels, and for nuclear factor (NF)-κB immunostaining. KEY FINDINGS: 1,8-cineole effectively reduced the cerulein-induced histological damage, pancreatic edema and NF-κB expression, levels of MPO activity and MDA, and replenished the GSH depletion. Cerulein increased serum levels of amylase and lipase, and pro-inflammatory cytokines TNF-α, IL-1ß, and IL-6 were also decreased by 1,8-cineole pretreatment, similar to thalidomide, a TNF-α inhibitor. The anti-inflammatory IL-10 cytokine level was, however, enhanced by 1,8-cineole. SIGNIFICANCE: These findings indicate that 1,8-cineole can attenuate cerulein-induced AP via an anti-inflammatory mechanism and by combating oxidative stress. Further studies are needed to clearly elucidate its benefits in patients on acute pancreatitis.
Assuntos
Ceruletídeo/toxicidade , Cicloexanóis/uso terapêutico , Citocinas/metabolismo , Monoterpenos/uso terapêutico , NF-kappa B/metabolismo , Estresse Oxidativo/fisiologia , Pancreatite/metabolismo , Pancreatite/prevenção & controle , Animais , Cicloexanóis/farmacologia , Citocinas/fisiologia , Eucaliptol , Masculino , Camundongos , Monoterpenos/farmacologia , NF-kappa B/fisiologia , Estresse Oxidativo/efeitos dos fármacos , Pancreatite/induzido quimicamenteRESUMO
BACKGROUND: Pentacyclic triterpenes in general exert beneficial effects in metabolic disorders. This study investigated the effects of α, ß-amyrin, a pentacyclic triterpene mixture from the resin of Protium heptaphyllum on blood sugar level and lipid profile in normal and streptozotocin (STZ)-induced diabetic mice, and in mice fed on a high-fat diet (HFD). FINDINGS: Mice treated with α, ß-amyrin (10, 30 and 100 mg/kg, p.o.) or glibenclamide (10 mg/kg, p.o.) had significantly reduced STZ-induced increases in blood glucose (BG), total cholesterol (TC) and serum triglycerides (TGs). Unlike glibenclamide that showed significant reductions in BG, TC and TGs in normoglycemic mice, α, ß-amyrin did not lower normal blood sugar levels but at 100 mg/kg, manifested a hypolipidemic effect. Also, α, ß-amyrin effectively reduced the elevated plasma glucose levels during the oral glucose tolerance test. Moreover, the plasma insulin level and histopathological analysis of pancreas revealed the beneficial effect of α, ß-amyrin in the preservation of beta cell integrity. In mice treated orally with α, ß-amyrin (10, 30 and 100 mg/kg) or fenofibrate (200 mg/kg), the HFD-associated rise in serum TC and TGs were significantly less. The hypocholesterolemic effect of α, ß-amyrin appeared more prominent at 100 mg/kg with significant decreases in VLDL and LDL cholesterol and an elevation of HDL cholesterol. Besides, the atherogenic index was significantly reduced by α, ß-amyrin. CONCLUSIONS: These findings reflect the potential antihyperglycemic and hypolipidemic effects of α, ß-amyrin mixture and suggest that it could be a lead compound for drug development effective in diabetes and atherosclerosis.
Assuntos
Hipoglicemiantes/farmacologia , Hipolipemiantes/farmacologia , Magnoliopsida/química , Ácido Oleanólico/análogos & derivados , Animais , Glicemia/metabolismo , Colesterol/sangue , Diabetes Mellitus Experimental/sangue , Diabetes Mellitus Experimental/tratamento farmacológico , Diabetes Mellitus Experimental/patologia , Dieta Hiperlipídica/efeitos adversos , Descoberta de Drogas , Fenofibrato/farmacologia , Glibureto/farmacologia , Hipercolesterolemia/sangue , Hipercolesterolemia/tratamento farmacológico , Hipoglicemiantes/administração & dosagem , Hipoglicemiantes/química , Hipolipemiantes/administração & dosagem , Hipolipemiantes/química , Células Secretoras de Insulina/efeitos dos fármacos , Células Secretoras de Insulina/patologia , Masculino , Camundongos , Ácido Oleanólico/administração & dosagem , Ácido Oleanólico/química , Ácido Oleanólico/farmacologia , Fitoterapia , Triglicerídeos/sangueRESUMO
AIM: To study the beneficial effects of triterpene alpha,beta-amyrin and the underlying mechanisms in an experimental pancreatitis model. METHODS: Acute pancreatitis was induced in five groups of rats (n = 8) by L-arginine (2 x 2.5 g/kg, intraperitoneal, 1 h apart) and 1 h later, they received a single oral dose of alpha,beta-amyrin (10, 30 and 100 mg/kg), methylprednisolone (30 mg/kg) and vehicle (3% Tween 80). A saline (0.9% NaCl) treated group served as a normal control. Efficacy was assessed at 24 h by determination of serum levels of amylase, lipase and pro-inflammatory cytokines [tumor necrosis factor (TNF)-alpha and interleukin (IL)-6], pancreatic myeloperoxidase (MPO) activity, lipid peroxidation [thiobarbituric acid reactive substances (TBARS)], nitrate/nitrite levels, and the wet weight/body weight ratio. Tissue histology and the immunoreactivity for TNF-alpha and inducible nitric oxide synthetase (iNOS) were performed. RESULTS: alpha,beta-amyrin and methylprednisolone treatments significantly (P < 0.05) attenuated the L-arginine-induced increases in pancreatic wet weight/body weight ratio, and decreased the serum levels of amylase and lipase, and TNF-alpha and IL-6, as compared to the vehicle control. Also, pancreatic levels of MPO activity, TBARS, and nitrate/nitrite were significantly lower. Histological findings and TNF-alpha and iNOS immunostaining further confirmed the amelioration of pancreatic injury by alpha,beta-amyrin. CONCLUSION: alpha,beta-amyrin has the potential to combat acute pancreatitis by acting as an anti-inflammatory and antioxidant agent.